Reductive Intramolecular Henry Reactions Induced by Stryker’s Reagent

Abstract

Conjugate reductions of nitroalkenes by Stryker’s reagent are ensued by intramolecular aldol reactions to produce β-nitroalcohols in good yield, constituting the first examples of reductive Henry reactions.

Key words

nitro-aldol reactions - reductions - tandem reactions - copper - nitroalkenes

References

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19

Typical Experiment Procedure: Compound 1 (1.5 hydride equiv) was transferred to a dry flask inside a dry box. Toluene (2 mL) was added and the resulting red solution was cooled to -40 °C. Nitroalkene 2a (0.6 mmol) in 2 mL toluene was added to 1 via cannula. After 1 h, the reaction was quenched by adding 2 mL sat. aq NH₄Cl and stirred for 2 h open to air. The resultant mixture was filtered through a silica gel pad and concentrated in vacuo. Flash chromatography of the residue (5% EtOAc in hexane) afforded c -3a (two isomers) and t -3a as colorless oils.
c -3a (β-NO₂): R _f = 0.66 (20% EtOAc in hexane). IR (CH₂Cl₂): 3551, 2943, 2873, 1606, 1546, 1453, 1378 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 5.17 (dd, J = 12.9, 3.7 Hz, 1 H), 2.92 (s, 1 H), 2.41 (qd, J = 13.0, 4.6 Hz, 1 H), 2.01-1.94 (m, 1 H), 1.88 (td, J = 13.8, 4.9 Hz, 1 H), 1.79 (td, J = 13.9, 4.4 Hz, 1 H), 1.75-1.64 (m, 3 H), 1.64-1.55 (m, 3 H), 1.55-1.43 (m, 1 H), 1.35 (dt, J = 14.0, 3.1 Hz, 1 H), 1.17-1.10 (m, 2 H), 1.08 (s, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 87.3, 73.6, 39.0, 34.8, 32.9, 31.9, 27.3, 23.2, 22.1, 20.8, 19.7. MS (EI, 20 eV): m/z (%) = 213 (2) [M⁺], 196 (1), 167 (7), 149 (100). HRMS (EI): m/z calcd for C₁₁H₁₉NO₃ [M⁺]: 213.1365; found: 213.1353.
c -3a (α-NO₂): R _f = 0.57 (20% EtOAc in hexane). IR (CH₂Cl₂): 3563, 2937, 2869, 1606, 1545, 1453, 1370 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 4.73 (dd, J = 12.0, 5.3 Hz, 1 H), 2.77 (s, 1 H), 2.10 (m, 1 H), 2.06 (qd, J = 13.4, 5.0 Hz, 1 H), 1.96 (td, J = 13.7, 4.6 Hz, 1 H), 1.87-1.53 (m, 6 H), 1.49-1.38 (m, 2 H), 1.22-1.12 (m, 2 H), 1.09 (dm, J = 13.7 Hz, 1 H), 1.08 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 90.8, 74.7, 39.2, 36.3, 32.3, 27.5, 27.2, 22.4, 21.1, 21.0, 19.3. MS (EI, 20 eV): m/z (%) = 196 (0.2) [M⁺ - OH], 167 (17), 149 (100). HRMS (EI): m/z calcd for C₁₁H₁₈NO₂ [M⁺ - OH]: 196.1338; found: 196.1326. t -3a: R _f = 0.71 (20% EtOAc in hexane). IR (CH₂Cl₂): 3559, 2948, 2869, 1542, 1483, 1446, 1373 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 4.68 (dd, J = 12.8, 4.1 Hz, 1 H), 2.60 (s, 1 H), 2.47 (qd, J = 12.6, 7.1 Hz, 1 H), 2.01-1.96 (m, 1 H), 1.91-1.78 (m, 2 H), 1.78-1.73 (m, 1 H), 1.73-1.66 (m, 2 H), 1.66-1.60 (m, 1 H), 1.59-1.46 (m, 3 H), 1.25-1.20 (m, 1 H), 1.07-1.03 (m, 1 H), 1.03 (s, 3 H), 0.98 (dt, J = 13.1, 3.3 Hz, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 90.0, 73.0, 38.2, 34.9, 32.9, 29.6, 27.2, 20.6, 20.3, 19.5, 19.1. MS (EI, 20 eV): m/z (%) = 196 (0.2) [M⁺ - OH], 167 (8), 149 (100). HRMS (EI): m/z calcd for C₁₁H₁₈NO₂ [M⁺ - OH]: 196.1338; found: 196.1302. The relative stereochemistries of c -3a (β-NO₂), c -3a (α-NO₂), t -3a (β-NO₂), and all other cyclized compounds 3 were determined by 2-D NOE spectral correlations.

21

The different ratios of diastereomeric products obtained under the two reaction conditions (Table [1] , entry 2 and Equation [2] ) implies that t -3b is the kinetic product and that the thermodynamic energies of c -3b and t -3b are comparable. That t -3b is the kinetic product was further confirmed by being the only product isolated when the reduction of 2b at -40 °C was quenched after 15 min. The optimized configurations of t -3b and c -3b by DFT calculations using the B3LYP/6-31G (d) model showed that t -3b was thermodynamically more stable than c -3b by 2.1 kcal/mol.